Penetrance and outcomes at 1-year following return of actionable variants identified by genome sequencing

• Published in: Genetics in medicine Vol. 23; no. 7; pp. 1192 - 1201
• Main Authors: Lee, Christopher, Elsekaily, Omar, Kochan, David C., Alhalabi, Lubna, Faizee, Faizan, Sharp, Richard, Lindor, Noralane M., Kullo, Iftikhar J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.07.2021; Elsevier Limited
• Subjects: Electronic health records; Genome; Genomics; Humans; Penetrance; Phenotype
• ISSN: 1098-3600; 1530-0366
• DOI: 10.1038/s41436-021-01142-9

We estimated penetrance of actionable genetic variants and assessed near-term outcomes following return of results (RoR). Participants (n = 2,535) with hypercholesterolemia and/or colon polyps underwent targeted sequencing of 68 genes and 14 single-nucleotide variants. Penetrance was estimated based on presence of relevant traits in the electronic health record (EHR). Outcomes occurring within 1-year of RoR were ascertained by EHR review. Analyses were stratified by tier 1 and non–tier 1 disorders. Actionable findings were present in 122 individuals and results were disclosed to 98. The average penetrance for tier 1 disorder variants (67%; n = 58 individuals) was higher than in non–tier 1 variants (46.5%; n = 58 individuals). After excluding 45 individuals (decedents, nonresponders, known genetic diagnoses, mosaicism), ≥1 outcomes were noted in 83% of 77 participants following RoR; 78% had a process outcome (referral to a specialist, new testing, surveillance initiated); 68% had an intermediate outcome (new test finding or diagnosis); 19% had a clinical outcome (therapy modified, risk reduction surgery). Risk reduction surgery occurred more often in participants with tier 1 than those with non–tier 1 variants. Relevant phenotypic traits were observed in 57% whereas a clinical outcome occurred in 19% of participants with actionable genomic variants in the year following RoR.